Haifa University Researchers Find Important Link In Fight Against Alzheimer’s

Alzheimer’s disease is considered incurable. However, researchers at Haifa University may have discovered a starting point towards an eventual treatment. During the study, conducted at the University of Haifa’s Sagol Department of Neurobiology, a link has been discovered between Alzheimer’s disease and the activity level of a protein called eIF2alpha. According to Prof. Kobi Rosenblum, head of the Department, altering the performance of this protein via drug therapy could constitute a treatment for Alzheimer’s. The study was published in the journal Neurobiology of Aging.

In recent years, Alzheimer’s research has primarily focused on battling the disease once symptoms have appeared, even though it’s known that the disease nests in the brain many years before any symptoms are revealed. In advanced stages of the disease, Prof. Rosenblum explains, small lumps (called plaques) are identified forming in the brain from a protein called amyloid. These plaques, he says, are typical in Alzheimer’s patients and undermine brain functioning. Much research has been directed at understanding these plaques and trying to eliminate them or restrict their formation and growth.
The new study, conducted by research student Yifat Segev in the Laboratory for Research of Molecular and Cellular Mechanisms Underlying Learning and Memory, which is headed by Prof. Rosenblum, in cooperation with Prof. Danny Michaelson of Tel Aviv University, sought to identify factors that could be linked to Alzheimer’s even before the irreversible amyloid plaques are formed, and that are connected to the disease’s primary risk factor – age.
Promising results
A previous study co-authored by Canadian researchers and Prof. Rosenblum’s lab at the University of Haifa, revealed that cognitive abilities could be improved by altering the activity of the eIF2alpha protein, which regulates the creation of proteins in all cells, including nerve cells. That research gave Alzheimer’s researchers a glimmer of hope: Perhaps it would be possible to improve cognitive abilities or even prevent cognitive damage in Alzheimer’s patients at an early stage of the disease by intervening in the mechanisms that regulate protein generation in nerve cells.
The current study compared mice that expressed the human Apoe4 gene – a gene known as a central risk factor for Alzheimer’s – with a group of mice with the parallel Apoe3 gene, which does not constitute a risk factor for the disease. Mice in the former group showed a change in the regulating mechanism for protein generation involving the eIF2alpha protein that damaged the cognitive abilities of those mice at a young age. This sort of mechanism change is characteristic of aging, and so also hinted at the tendency of these mice toward premature aging.
According to Segev, this is the first time that a link has been found between the activity of eIF2alpha and the Apoe4 gene in relation to Alzheimer’s disease. She noted that modification treatments for the eIF2alpha mechanism are being widely researched and are developing quickly, and so the more we can understand about the connection between this mechanism and Alzheimer’s, the more we can find ways to identify and slow the progress of the disease.

Study Finds Precious Stem Cells Are Assigned ‘Bodyguard’ Cells

Hiding deep inside our bone marrow — the flexible tissue found in the interior of bones — are special cells. They wait patiently for the hour of need, at which point these blood forming stem cells can proliferate and differentiate into billions of mature blood cells to help the body cope with infection, for example, or they can turn into extra red blood cells for low oxygen levels at high altitudes.

Even in emergencies, however, the body sticks to a long-term plan: It maintains a reserve of undifferentiated stem cells, meaning cells that have not yet expressed signs of their future specific type, for eventual needs and crises.

A research team headed by Prof. Tsvee Lapidot of Israel’s Weizmann Institute’s immunology Department recently discovered a new type of bodyguard that protects stem cells from over-differentiation. In a paper that appeared in Nature Immunology, they revealed how this rare, previously unknown sub-group of activated immune cells keeps the stem cells in the bone marrow “forever young.”

Blood forming stem cells live in comfort in the bone marrow, surrounded by an entourage of support cells that cater to their needs and direct their development – the mesenchymal cells. But the research team, which included postdoctoral fellow Dr. Aya Ludin, Prof. Steffen Jung of the Immunology Department and his group, and Ziv Porat of the Biological Services Unit, discovered another type of support cell for the stem cells. These are an offshoot of the macrophage family, literally the “big eaters” of the immune system that are important, for instance, for bacterial clearance.

The team found, however, that a rare sub-population of the bone-marrow macrophages has another role to play. Each of these rare macrophages can take a stem cell under its wing and prevent its differentiation.

Keeping useful cells alive during chemotherapy

Probing more deeply, the researchers revealed, in precise detail, how these macrophages guard the stem cells. They secrete substances called prostaglandins, which are absorbed by the stem cells. In a chain of biochemical events, these substances delay differentiation and preserve the youthful state of the stem cells. In addition, the prostaglandins work on the neighboring mesenchymal cells, activating the secretion of a delaying substance in them and increasing the production of receptors for this substance on the stem cells, themselves.

This activity, says Lapidot, may help the non-dividing stem cells survive chemotherapy – a known phenomenon. Macrophages also live through the treatment, and they respond by increasing their prostaglandin output, thus heightening their vigilance in protecting the stem cells.

The bodyguard macrophages also increase their activity in times of infection. While other members of the macrophage family are recruited to fight the pathogens, their cousins in the bone marrow are hard at work ensuring that a pool of stem cells will resist the urge to differentiate.

In previous work in Lapidot’s lab, it was discovered that prostaglandin treatments can improve the number and quality of stem cells. This insight is currently being tested by doctors in clinical transplantation trials for the use of stem cells from umbilical cord blood to treat adult leukemia patients. These trials are showing that prior treatment with prostaglandins improves migration and repopulation potential, enabling the small quantities of cord blood stem cells to better cure the patients.

“The present study hints at the possibility of further increasing the support for bone marrow stem cells by exploring this intriguing connection between the immune cells and stem cells,” says Lapidot. “An understanding of the mechanisms at work in these cells might improve the success of stem cell transplantation, especially that of umbilical blood.”